The epithelial cell adhesion molecule EpCAM (also known as CD326 or ESA) is a pleiotropic molecule, capable of both promoting and preventing epithelial cell-cell adhesion. It is a 30-40 kDa type I glycosylated membrane protein expressed at a low level in a variety of human epithelial tissues. EpCAM is overexpressed in most solid cancers. For example, intense expression of EpCAM is found in more than 98% of patients with colorectal cancer. Two decades of studies have shed light on the roles the EpCAM plays in tumorigenesis. Rather than antagonising apoptosis, EpCAM acts by inducing proliferation with a direct impact on cell cycle control upregulating the proto-oncogene c-myc and cyclins A and E, and signal transduction into the cell nucleus by way of the Wnt pathway.
It has recently been recognised that a small proportion of cancer cells possess unlimited proliferation potential and are able to self-renewal and to generate differentiated cancer cell progeny. These so-called cancer stem cells (CSCs) are resistant to chemotherapy and radiotherapy. It is thought that cytotoxic drugs and radiation kill mainly the bulk tumor cells but spare the cancer stem cells. Thus, in order to effectively eradicate cancer, one must target and eliminate cancer stem cells as well as their progeny cells.
Epithelial cell adhesion molecule has been identified to be a cancer stem cell marker in a number of solid cancers, including breast cancer, colorectal cancer, pancreatic cancer, and liver cancer. Expression of EpCAM in various cancers appears to be inversely related to the prognosis of the patients (Baeuerle P A et al (2007). Br J Cancer 96:417-23). Initial clinical trials with anti-EpCAM antibodies failed to provide objective clinical response. It is thought that the large size of the antibody is a limitation to the distribution and delivery of monoclonal antibodies. In addition, the antibody dependent cytotoxicity relies on the carbohydrate composition in the CH2 of the antibody, which can vary significantly during antibody production. Thus, a smaller and more effective EpCAM targeting molecule is needed for targeted cancer therapy.